The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.
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This work was supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT) grants RR150010, RP210199 and RP19023, the Department of Defense grants W81XWH-21-1-0332/0333 and W81XWH-17-1-0401, the Susan G. Komen Foundation Career Catalyst Research grant CCR19605871 and the National Cancer Institute grant 1K08CA241070. R.F.M. is a CPRIT Established Investigator. Research reported in this publication was also supported by the Children’s Cancer Fund Comprehensive Center for Pediatric Oncology Research. The authors acknowledge Siemens Medical Solutions USA for the Siemens Sequoia ultrasound scanner loan. The authors acknowledge the UT Southwestern Harold C. Simmons Cancer Center Support grant P30 CA142543 for the support provided by the Small Animal Imaging shared resource. The authors also would like to acknowledge Erin Moore (Creatives Services, Department of Radiology, The University of Texas Southwestern Medical Center) for the illustrations in Fig. 1a,b and Supplementary Fig. 5a, and C. Wogan from the MD Anderson Cancer Center for editorial help.
A provisional patent application based on the technology described in the manuscript has been filed by The University of Texas Southwestern Medical Center, with S.K., J.L. and W.J. as inventors, application number 63/173,956. All other authors declare no competing interests.
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Li, X., Khorsandi, S., Wang, Y. et al. Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles. Nat. Nanotechnol. (2022). https://doi.org/10.1038/s41565-022-01134-z